Moderna makes rare diseases push in follow-up to Covid vaccine success

Just a few years ago, Moderna faced a chorus of doubts over whether its experimental mRNA technology would ever work well enough to become a medicine. After the $36 billion success of its Covid-19 vaccines, the question now becomes: What’s next?

The biotech’s answer over the past year has been “more of everything,” including an expansive infectious disease vaccine pipeline and developing personalized cancer vaccines with Merck. And now, early signs of success using the messenger molecule to make therapeutic proteins in the liver have Moderna ecstatic about yet another application for mRNA.

“We’re going full steam in rare disease,” CEO Stéphane Bancel told Endpoints News in an exclusive interview. “Moderna will be a rare disease company.”

Last month, the company revealed an encouraging glimpse from an early-stage study of its therapy that helps children born with a metabolic disease make a crucial enzyme their bodies are missing. Infusions every other week of an mRNA molecule encoding the enzyme reduced dangerous and sometimes deadly metabolic crises by about 66%.

It was the green light that Moderna was waiting for.

“The clinical signal is there,” Bancel said. “We are doubling down, if not tripling down or quadrupling down, on rare disease.”

Moderna’s push comes as numerous companies – from nimble biotechs to pharma giants like Pfizer – have trimmed their rare disease pipelines. Bancel is mRNA’s most enthusiastic salesman, and investors have learned to take his proclamations with a grain of salt. Yet with roughly $16.4 billion in cash and long- and short-term investments as of March 31, Moderna has the financial firepower to write its next chapter.

“Moderna needs to succeed here,” Myles Minter, an analyst at William Blair, said in an interview. “There is money to be made in rare diseases – more than $130 a dose for a vaccine. If you can create a pipeline of rare disease assets, you could potentially build the next Genzyme,” he added, referencing the legendary biotech.

The biotech has already been laying the groundwork. Earlier this year, Moderna announced plans to bump its R&D budget to $4.5 billion and hire roughly 2,000 employees to increase its headcount by about 50%. While Bancel wouldn’t say how much he’s investing, the company already has three clinical, three preclinical, and several more undisclosed liver-targeted mRNA therapies for rare diseases.

Kyle Holen

“Our ambitions are quite large,” Kyle Holen, Moderna’s SVP and head of development for therapeutics and oncology, told Endpoints. “We have a whole pipeline of mRNAs in our preclinical development programs that will hopefully be coming to the clinic in the next year or two.”

Moderna is also building a rare disease commercial team helmed by Patricia Gauthier, who led Moderna’s operations in Canada during the pandemic, Bancel added. (The company is in the middle of other changes as well: On Tuesday, Amgen announced that it was hiring CMO Paul Burton, who had joined Moderna in 2021.)

“A tsunami of rare disease drugs”

One of the biggest selling points of mRNA technology is its programmability. Bancel frequently tells investors that if the company demonstrates safety and efficacy in one mRNA medicine, making more based on the same formulation and targeting the same part of the body should be easy. All they need to do is change the genetic sequence.

The approach is evident in Moderna’s increasingly large vaccine pipeline, with more than 30 candidates for roughly 15 infectious diseases, including flu, HIV and Lyme disease.

“It’s exactly the same strategy that we’ve talked about forever,” Bancel said. “We try to make sure that the technology works first. And if it does, then we will go after a lot of diseases.”

His 13-year-old company has long held that its mRNA technology could supply the genetic code for proteins that are broken or missing in people born with genetic conditions, though the development of these therapies has lagged behind its vaccine programs.

In 2021, Moderna finally dosed its first patients in trials for two rare diseases: propionic acidemia and methylmalonic acidemia. “If we get positive data in those two rare disease programs, then you will see a tsunami of rare disease drugs moving from the labs into the clinic,” Bancel told the Boston Globe last year.

Missing enzymes in both conditions cause the buildup of toxic molecules in the body, which can damage organs, including the brain. In May, the company presented the first interim data from a small study of its propionic acidemia therapy in 16 kids, suggesting that its mRNA therapy was working.

And just as importantly, although frequent infusions of the therapy had side effects, Moderna believes the drug is safe enough to move forward and unlock its broader ambitions.

“It gives us much more confidence in the ability to succeed across our entire rare disease portfolio,” Holen said.

Karen Andersen, an analyst who covers Moderna for Morningstar, was also encouraged. “Prior to this data, there was a lot of skepticism,” she said. “It creates a really interesting niche for them, and it opens the door to all sorts of proteins or antibodies they could potentially make.”

Other scientists found the preliminary results vague.

Harvey Lodish

“There are just huge uncertainties,” including whether there are immune responses to the therapy, said Harvey Lodish, a scientist and biotech entrepreneur at the Whitehead Institute who was involved in the early days of Genzyme.

Lodish also questioned whether mRNA would have an advantage over protein replacement therapies that are taken chronically or viral vector-based gene therapies, which are designed to be permanent, one-time treatments. “It is not clear that injecting patients with mRNA every other week will be any more effective,” he said.

“All kids stayed on the drug”

Despite Moderna’s excitement, questions also remain about the safety and tolerability of a chronic mRNA therapy, largely due to the microscopic balls of natural and synthetic fats called lipid nanoparticles, or LNPs, which help protect and shuttle the mRNA molecule into cells.

LNPs were linked to the reactions many people experienced after getting Moderna’s Covid shot. And although many people put up with fevers and fatigue from the vaccines during the pandemic, patients might not tolerate more frequent reactions from mRNA drugs that need to be dosed once or twice a month.

“People have always wanted to use mRNA as a therapeutic, but the issue has been immunogenicity,” Minter said.

By Moderna’s account, biweekly dosing of its propionic acidemia therapy, dubbed mRNA-3927, was deemed safe. But there were frequent side effects experienced by almost all 16 patients in the trial, including fever, diarrhea, and vomiting. And half experienced severe adverse events, including one patient who developed severe pancreas inflammation from the drug.

Kathryn Whitehead

Kathryn Whitehead, a gene delivery scientist at Carnegie Mellon University, told Endpoints that while the reactions were “not ideal,” she said the study was too small and it was “hard to make any conclusion on clinical viability based on these data.”

Six patients also experienced infusion-related reactions, which typically only occurred once or twice but arose 11 times in one participant. Holen described those reactions as expected but manageable using inflammation-lowering medications or by spacing out dosing.

“We view this as maybe more of a minor problem, as opposed to a major problem,” Holen said.

Lodish, the Whitehead researcher, was less sure. “That’s not terribly encouraging,” she said. “This is uncharted territory. It’s like getting the equivalent of a vaccine every two weeks for the rest of your life.”

The doses for mRNA therapies are also much higher than for vaccines. While Moderna’s Covid booster shots were 50 micrograms, the company tested doses ranging from 300 to 900 micrograms per kilogram of body weight in its propionic acidemia therapy, meaning patients got doses of mRNA-filled lipid nanoparticles roughly 60 to 1,600 times what’s used in the Covid boosters.

Jerry Vockley

Moderna said that the families of all 11 patients who have finished the study — which ranges from 20 to 40 weeks — have opted for their children to continue receiving the infusions in an open-label extension.

“The acid test, in my opinion, is that all kids stayed on the drug,” Bancel said.

But from the patient’s perspective, the bar for safety and side effects will be higher for some diseases, said Jerry Vockley, chief of medical genetics at UPMC Children’s Hospital of Pittsburgh, who has worked with Moderna on preclinical tests of mRNA therapies for two disorders of fatty acid metabolism called VLCAD and MCAD deficiencies.

Many doctors and patients perceive MCAD to be a mild condition, Vockley said, and he told Moderna that their jointly-made mRNA therapy for the disease might be hard to bring to market.

Others have questioned how much of an impact on the company’s profits can be found for drugs for very small patient populations.

“They’ll need a lot of them to drive growth,” said Hartaj Singh, an analyst who covers Moderna for Oppenheimer. But he said that rare diseases could still be “extremely important” for the company’s valuation since Moderna may be the only company willing and ready to tackle a full slate of rare diseases with mRNA.

‘Everything’s on the table’

Moderna began a clinical trial for a third metabolic condition called glycogen storage disease type 1a in 2022. The company’s three preclinical programs for ornithine transcarbamylase deficiency, phenylketonuria, and Crigler-Najjar syndrome type 1 are also caused by missing liver enzymes. They’re just a few of the roughly 1,500 genetic diseases caused by mutations that disrupt the body’s ability to make or break down molecules.

“I’m not going to tell you that we have a pipeline of 1,500 mRNA therapies. That would be a little bit ridiculous,” Holen said. “But everything’s on the table.”

Some of Moderna’s interests in rare diseases have been revealed in scientific papers published by academic researchers that have partnered with the company, including UPMC’s Vockley.

Vockley thinks mRNA therapies will be relatively fast to design and easy to stop taking if safety issues arise, which could give them a leg up on one-and-done gene therapies.

“The big issue with mRNA right now is that it is limited to liver delivery,” he said, but estimated that at least 50 to 100 genetic metabolic diseases could be treated in that organ.

“If either kids or parents are suffering, and it’s a liver-induced lack of function, we’re going to go after it,” Bancel said.

Some diseases may be too rare for Moderna to pursue commercially, but Bancel emphasized that his company is committed to finding another way to get those therapies into the clinic. He points to 2021, when Moderna donated its preclinical therapy for Crigler-Najjar syndrome type 1 to the Institute for Life Changing Medicines, the nonprofit dedicated to treating ultra-rare diseases co-founded by Jim Wilson, a gene therapy pioneer at the University of Pennsylvania.

Bancel said Moderna could strike more “Penn-like partnerships” in the future. He is also thinking about how to make drugs for conditions that only affect 10 people or fewer — sometimes just one person. The company has already received calls from academics asking if Moderna could make so-called n-of-1 therapies. Bancel believes that it can.

The company has machines dedicated to making custom mRNA therapies for its cancer vaccines, which train a patient’s immune system to target the unique molecular blueprint of their tumors. Bancel said those machines could be applied to rare diseases, especially for diseases with so few patients that they are essentially custom-made.

Timothy Yu

Timothy Yu, a researcher at Boston Children’s Hospital who has spearheaded the development of customized therapies for children with unique genetic mutations, finds Moderna’s vision exciting. Like others in the N-of-1 field, Yu has largely employed antisense oligonucleotides, which can coax cells to skip over certain genetic typos or shut down disease-causing genes. But the approach requires a deep understanding of the cause of a person’s disease and doesn’t work for every mutation.

“If we can really figure out how to make this work at scale for many different diseases, it has the potential to be — dare I say — the silver bullet for treating this long tail of incredibly rare conditions,” Yu said.

But other biotech companies have taken on genetic therapies for ultra-rare diseases, only to shelve the programs when money got tight, leaving the families who helped kick-start those experimental treatments hanging.

“We need to figure out the resources and time and cost involved,” Bancel said.

The company would also need regulators to approve the trials, although he points to Moderna’s individualized cancer vaccines as precedent.

“The path might be long, but there will be a path,” Bancel said.

“We’re going to become a very big rare disease company,” he added. “And we’re very committed to those families and those kids.”

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